Sirtuin1 Suppresses Calcium Oxalate Nephropathy via Inhibition of Renal Proximal Tubular Cell Ferroptosis Through PGC‐1α‐mediated Transcriptional Coactivation
Abstract Calcium oxalate (CaOx) crystals induce renal tubular epithelial cell injury and subsequent nephropathy. However, the underlying mechanisms remain unclear. In the present study, single‐cell transcriptome sequencing is performed on kidney samples from mice with CaOx nephrocalcinosis. Renal pr...
Saved in:
| Main Authors: | , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Wiley
2024-12-01
|
| Series: | Advanced Science |
| Subjects: | |
| Online Access: | https://doi.org/10.1002/advs.202408945 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1850086441774743552 |
|---|---|
| author | Chen Duan Bo Li Haoran Liu Yangjun Zhang Xiangyang Yao Kai Liu Xiaoliang Wu Xiongmin Mao Huahui Wu Zhenzhen Xu Yahua Zhong Zhiquan Hu Yan Gong Hua Xu |
| author_facet | Chen Duan Bo Li Haoran Liu Yangjun Zhang Xiangyang Yao Kai Liu Xiaoliang Wu Xiongmin Mao Huahui Wu Zhenzhen Xu Yahua Zhong Zhiquan Hu Yan Gong Hua Xu |
| author_sort | Chen Duan |
| collection | DOAJ |
| description | Abstract Calcium oxalate (CaOx) crystals induce renal tubular epithelial cell injury and subsequent nephropathy. However, the underlying mechanisms remain unclear. In the present study, single‐cell transcriptome sequencing is performed on kidney samples from mice with CaOx nephrocalcinosis. Renal proximal tubular cells are identified as the most severely damaged cell population and are accompanied by elevated ferroptosis. Further studies demonstrated that sirtuin1 (Sirt1) effectively reduced ferroptosis and CaOx crystal‐induced kidney injury in a glutathione peroxidase 4 (GPX4)‐dependent manner. Mechanistically, Sirt1 relies on peroxisome proliferator‐activated receptor gamma coactivator 1α (PGC‐1α) to promote resistance to ferroptosis in the tubular epithelium, and PGC‐1α can recruit nuclear factor erythroid 2‐related factor 2 (NRF2) to the promoter region of GPX4 and co‐activate GPX4 transcription. This work provides new insight into the mechanism of CaOx crystal‐induced kidney injury and identifies Sirt1 and PGC‐1α as potential preventative and therapeutic targets for crystal nephropathies. |
| format | Article |
| id | doaj-art-cf392b9a57464484acb45c9d8d97e0f9 |
| institution | DOAJ |
| issn | 2198-3844 |
| language | English |
| publishDate | 2024-12-01 |
| publisher | Wiley |
| record_format | Article |
| series | Advanced Science |
| spelling | doaj-art-cf392b9a57464484acb45c9d8d97e0f92025-08-20T02:43:28ZengWileyAdvanced Science2198-38442024-12-011148n/an/a10.1002/advs.202408945Sirtuin1 Suppresses Calcium Oxalate Nephropathy via Inhibition of Renal Proximal Tubular Cell Ferroptosis Through PGC‐1α‐mediated Transcriptional CoactivationChen Duan0Bo Li1Haoran Liu2Yangjun Zhang3Xiangyang Yao4Kai Liu5Xiaoliang Wu6Xiongmin Mao7Huahui Wu8Zhenzhen Xu9Yahua Zhong10Zhiquan Hu11Yan Gong12Hua Xu13Department of Radiation and Medical Oncology Zhongnan Hospital of Wuhan University Wuhan Hubei 430071 ChinaTumor Precision Diagnosis and Treatment Technology and Translational Medicine Hubei Engineering Research Center Zhongnan Hospital of Wuhan University Wuhan Hubei 430071 ChinaSchool of Medicine Stanford University Stanford CA 94303 USATumor Precision Diagnosis and Treatment Technology and Translational Medicine Hubei Engineering Research Center Zhongnan Hospital of Wuhan University Wuhan Hubei 430071 ChinaTumor Precision Diagnosis and Treatment Technology and Translational Medicine Hubei Engineering Research Center Zhongnan Hospital of Wuhan University Wuhan Hubei 430071 ChinaTumor Precision Diagnosis and Treatment Technology and Translational Medicine Hubei Engineering Research Center Zhongnan Hospital of Wuhan University Wuhan Hubei 430071 ChinaDepartment of Urology Tongji Hospital Tongji Medical College Huazhong University of Science and Technology Wuhan Hubei 430011 ChinaTumor Precision Diagnosis and Treatment Technology and Translational Medicine Hubei Engineering Research Center Zhongnan Hospital of Wuhan University Wuhan Hubei 430071 ChinaTumor Precision Diagnosis and Treatment Technology and Translational Medicine Hubei Engineering Research Center Zhongnan Hospital of Wuhan University Wuhan Hubei 430071 ChinaTumor Precision Diagnosis and Treatment Technology and Translational Medicine Hubei Engineering Research Center Zhongnan Hospital of Wuhan University Wuhan Hubei 430071 ChinaDepartment of Radiation and Medical Oncology Zhongnan Hospital of Wuhan University Wuhan Hubei 430071 ChinaDepartment of Urology Tongji Hospital Tongji Medical College Huazhong University of Science and Technology Wuhan Hubei 430011 ChinaTumor Precision Diagnosis and Treatment Technology and Translational Medicine Hubei Engineering Research Center Zhongnan Hospital of Wuhan University Wuhan Hubei 430071 ChinaTumor Precision Diagnosis and Treatment Technology and Translational Medicine Hubei Engineering Research Center Zhongnan Hospital of Wuhan University Wuhan Hubei 430071 ChinaAbstract Calcium oxalate (CaOx) crystals induce renal tubular epithelial cell injury and subsequent nephropathy. However, the underlying mechanisms remain unclear. In the present study, single‐cell transcriptome sequencing is performed on kidney samples from mice with CaOx nephrocalcinosis. Renal proximal tubular cells are identified as the most severely damaged cell population and are accompanied by elevated ferroptosis. Further studies demonstrated that sirtuin1 (Sirt1) effectively reduced ferroptosis and CaOx crystal‐induced kidney injury in a glutathione peroxidase 4 (GPX4)‐dependent manner. Mechanistically, Sirt1 relies on peroxisome proliferator‐activated receptor gamma coactivator 1α (PGC‐1α) to promote resistance to ferroptosis in the tubular epithelium, and PGC‐1α can recruit nuclear factor erythroid 2‐related factor 2 (NRF2) to the promoter region of GPX4 and co‐activate GPX4 transcription. This work provides new insight into the mechanism of CaOx crystal‐induced kidney injury and identifies Sirt1 and PGC‐1α as potential preventative and therapeutic targets for crystal nephropathies.https://doi.org/10.1002/advs.202408945crystal nephropathyferroptosisPGC‐1αrenal proximal tubular cellsSirt1 |
| spellingShingle | Chen Duan Bo Li Haoran Liu Yangjun Zhang Xiangyang Yao Kai Liu Xiaoliang Wu Xiongmin Mao Huahui Wu Zhenzhen Xu Yahua Zhong Zhiquan Hu Yan Gong Hua Xu Sirtuin1 Suppresses Calcium Oxalate Nephropathy via Inhibition of Renal Proximal Tubular Cell Ferroptosis Through PGC‐1α‐mediated Transcriptional Coactivation Advanced Science crystal nephropathy ferroptosis PGC‐1α renal proximal tubular cells Sirt1 |
| title | Sirtuin1 Suppresses Calcium Oxalate Nephropathy via Inhibition of Renal Proximal Tubular Cell Ferroptosis Through PGC‐1α‐mediated Transcriptional Coactivation |
| title_full | Sirtuin1 Suppresses Calcium Oxalate Nephropathy via Inhibition of Renal Proximal Tubular Cell Ferroptosis Through PGC‐1α‐mediated Transcriptional Coactivation |
| title_fullStr | Sirtuin1 Suppresses Calcium Oxalate Nephropathy via Inhibition of Renal Proximal Tubular Cell Ferroptosis Through PGC‐1α‐mediated Transcriptional Coactivation |
| title_full_unstemmed | Sirtuin1 Suppresses Calcium Oxalate Nephropathy via Inhibition of Renal Proximal Tubular Cell Ferroptosis Through PGC‐1α‐mediated Transcriptional Coactivation |
| title_short | Sirtuin1 Suppresses Calcium Oxalate Nephropathy via Inhibition of Renal Proximal Tubular Cell Ferroptosis Through PGC‐1α‐mediated Transcriptional Coactivation |
| title_sort | sirtuin1 suppresses calcium oxalate nephropathy via inhibition of renal proximal tubular cell ferroptosis through pgc 1α mediated transcriptional coactivation |
| topic | crystal nephropathy ferroptosis PGC‐1α renal proximal tubular cells Sirt1 |
| url | https://doi.org/10.1002/advs.202408945 |
| work_keys_str_mv | AT chenduan sirtuin1suppressescalciumoxalatenephropathyviainhibitionofrenalproximaltubularcellferroptosisthroughpgc1amediatedtranscriptionalcoactivation AT boli sirtuin1suppressescalciumoxalatenephropathyviainhibitionofrenalproximaltubularcellferroptosisthroughpgc1amediatedtranscriptionalcoactivation AT haoranliu sirtuin1suppressescalciumoxalatenephropathyviainhibitionofrenalproximaltubularcellferroptosisthroughpgc1amediatedtranscriptionalcoactivation AT yangjunzhang sirtuin1suppressescalciumoxalatenephropathyviainhibitionofrenalproximaltubularcellferroptosisthroughpgc1amediatedtranscriptionalcoactivation AT xiangyangyao sirtuin1suppressescalciumoxalatenephropathyviainhibitionofrenalproximaltubularcellferroptosisthroughpgc1amediatedtranscriptionalcoactivation AT kailiu sirtuin1suppressescalciumoxalatenephropathyviainhibitionofrenalproximaltubularcellferroptosisthroughpgc1amediatedtranscriptionalcoactivation AT xiaoliangwu sirtuin1suppressescalciumoxalatenephropathyviainhibitionofrenalproximaltubularcellferroptosisthroughpgc1amediatedtranscriptionalcoactivation AT xiongminmao sirtuin1suppressescalciumoxalatenephropathyviainhibitionofrenalproximaltubularcellferroptosisthroughpgc1amediatedtranscriptionalcoactivation AT huahuiwu sirtuin1suppressescalciumoxalatenephropathyviainhibitionofrenalproximaltubularcellferroptosisthroughpgc1amediatedtranscriptionalcoactivation AT zhenzhenxu sirtuin1suppressescalciumoxalatenephropathyviainhibitionofrenalproximaltubularcellferroptosisthroughpgc1amediatedtranscriptionalcoactivation AT yahuazhong sirtuin1suppressescalciumoxalatenephropathyviainhibitionofrenalproximaltubularcellferroptosisthroughpgc1amediatedtranscriptionalcoactivation AT zhiquanhu sirtuin1suppressescalciumoxalatenephropathyviainhibitionofrenalproximaltubularcellferroptosisthroughpgc1amediatedtranscriptionalcoactivation AT yangong sirtuin1suppressescalciumoxalatenephropathyviainhibitionofrenalproximaltubularcellferroptosisthroughpgc1amediatedtranscriptionalcoactivation AT huaxu sirtuin1suppressescalciumoxalatenephropathyviainhibitionofrenalproximaltubularcellferroptosisthroughpgc1amediatedtranscriptionalcoactivation |